Transdermal delivery devices for the delivery of a wide variety of biologically active agents have been known for some time and representative systems which utilize rate controlling membranes and in-line adhesives are disclosed in U.S. Pat. Nos. 3,598,122, 3,598,123, 3,742,951, 4,031,894, 4,060,084, 4,144,317, 4,201,211 and 4,379,454 which are incorporated herein by reference. Such devices generally comprise an impermeable backing, a drug or active agent reservoir, a rate controlling membrane and a contact adhesive layer which can be laminated or heat sealed together to produce a transdermal delivery device. Although subsaturated systems are known, see U.S. Pat. No. 4,379,454, for example, it is generally desirable that the agent reservoir comprise the agent to be delivered in a suitable carrier at a concentration above the saturation concentration in the carrier. This is done to maintain a unit activity source of the agent so that the delivery rate of the agent will remain substantially constant over the intended administration period; the amount of agent originally present over saturation being the depot or reservoir for the dose of agent ultimately delivered. If the concentration of the agent drops below unit activity during the delivery period, the rate of agent delivery will exhibit a corresponding decrease. It is also generally desirable to minimize the residual agent in the device after use and to accomplish this devices normally utilize, as a carrier, a material which has limited solubility for the agent to be delivered. Although such typical devices have been found useful for the delivery of a wide variety of agents, we have encountered significant problems in producing devices intended to deliver an agent which is capable of dissolving or plasticizing medically acceptable contact adhesives. Such agents are usually, but not always, oily, nonpolar materials, liquid at ambient temperatures, and are either solvents for medically acceptable contact adhesives or are highly soluble therein and cause such adhesives to loose their adhesiveness. In the latter case, the agent may not actually solvate the adhesive but instead plasticize the adhesive and cause it to swell, loose its cohesiveness and adhesiveness, and degrade its other physical properties. As used herein, an agent is a "solvent" for medically acceptable adhesives, and such adhesives are "soluble" in such agents if the agent either dissolves or plasticizes such adhesives as described above.
Agents which are such solvents may be drugs, permeation enhancers or other transdermally deliverable substances. Representative of such agents are drugs such as benztropine base, an anticholinergic useful in the treatment of Parkinsonism, the antispasmolytic drugs, secoverine and dexsecoverine, nicotine, useful in the withdrawal from smoking, and arecoline, a cholinergic and anthelminitic agent, and permeation enhancers such as polyethylene glycol monolaurate, glycerol monolaurate and glycerol monooleate. Ethanol, which is not an oily, nonpolar liquid, is an example of a permeation enhancer which, in high concentrations, can plasticize certain medically acceptable contact adhesives.
Regardless of the initial concentration of the agent in the reservoir and adhesive layers, the devices will equilibrate upon standing. Thus, if the agent is a solvent for the adhesive layer, we have found that substantial quantities migrate from the reservoir through the rate controlling membrane and into the adhesive layer prior to use. The migration will continue until the thermodynamic activity of the agent in the adhesive equals the activity of the agent in the reservoir. Thus, a substantial amount of agent can migrate into the adhesive layer and will be released onto the skin in an uncontrolled manner before the rate controlling membrane can exert any effect on the agent remaining in the reservoir. Also, high concentrations of agent in the adhesive layer and in direct contact with the skin may cause irritation or produce undesirably high plasma levels during the initial period after application to the skin and prior to depletion of the initial loading of agent in the contact adhesive layer. In addition to the deleterious effects on a patient that may be caused by high concentrations of agent in the adhesive, certain adhesives tend to loose their adhesive properties when they are dissolved or plasticized by the agent being delivered.
According to our invention, we have provided a rate controlled, subsaturated transdermal delivery device having an in-line adhesive which delivers an agent which is a solvent for the in-line adhesive and which exhibits improved release characteristics. In certain embodiments of our invention a substantially constant release rate over a substantial portion of a predetermined administration period can be obtained. The device utilizes a subsaturated reservoir containing a sufficient amount of agent to prevent the activity from decreasing by more than about 50% and preferably less than about 25% during the predetermined delivery period. The device is also typically designed such that no more than, and preferably substantially less than, half of the total agent loading in the device is in the adhesive and rate controlling membrane layers after equilibration and prior to use.
Preferred embodiments of our invention are rate controlled drug delivery devices having in-line adhesives for the controlled delivery of the anticholinergic, benztropine, and the tertiary amine secoverine, 1-cyclohexyl-4-C[ethyl(p-methoxy-alpha-methyl phenylethyl)amino]-butazone, an anti-spasmodic agent described in U.S. Pat. Nos. 3,996,245 and 4,125,623 which are incorporated herein by reference. The active, (d) isomer of secoverine is hereinafter referred to as "dexsecoverine". Attempts to produce transdermal delivery devices for these agents by following the aforementioned teachings of the prior art were unsuccessful based on a combination of the above considerations. It is also expected that similar problems will be encountered with respect to other agents which are solvents for medical adhesives.
It is accordingly an object of this invention to provide a rate controlled transdermal delivery device having an in-line adhesive and a subsaturated agent reservoir, which device exhibits improved delivery rate characteristics.
It is another object of this invention to provide a transdermal delivery device for the delivery of agents which are solvents or plasticizers for in-line adhesives.
It is another object of this invention to improve the delivery characteristics of a rate controlled, transdermal delivery device utilizing a subsaturated agent reservoir.